Revatio

Indications and Usage ( 1 ) 1/2023 Dosage and Administration ( 2.1 , 2.2 , 2.3 ) 1/2023

1 INDICATIONS AND USAGE Adults REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [see Clinical Studies (14) ] . Pediatric Patients (1 to 17 Years old) REVATIO is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients too young to perform standardized exercise testing, pulmonary hemodynamics thought to underlie improvements in exercise [see Clinical Studies (14) ] . Adults REVATIO is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening. ( 1 ) Pediatric Patients (1 to17 years old) REVATIO is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients too young to perform standard exercise testing, pulmonary hemodynamics thought to underlie improvements in exercise ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION • Adults: 20 mg three times a day Dose may be increased based on symptoms and tolerability. ( 2.1 ) • Pediatric patients ( 2.2 ) o ≤20 kg: 10 mg three times a day o 20 kg to 45 kg: 20 mg three times a day o >45 kg: 20 mg three times a day. Dose may be increased based on symptoms and tolerability. • Injection (Adults): 10 mg three times a day administered as an intravenous bolus injection. ( 2.1 ) 2.1 Recommended Dosage in Adults Oral Dosage The recommended dosage of REVATIO is 20 mg three times a day. Dose may be titrated to a maximum of 80 mg three times a day, if required, based on symptoms and tolerability [see Clinical Studies (14) ] . Although dose-response improvement in exercise ability was not observed in short-term studies in adults with PAH, the delay in clinical worsening with long-term use of sildenafil in Study A1481324 supports dosing up to a maximum of 80 mg three times a day [see Clinical Studies (14) ] . Intravenous Dosage The recommended dose is 10 mg administered as an intravenous bolus injection three times a day. The dose of REVATIO injection does not need to be adjusted for body weight . A 10-mg dose of REVATIO injection is predicted to provide pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20-mg oral dose . 2.2 Recommended Dosage in Pediatric Patients Oral Dosage The recommended dosage in patients ≤20 kg is 10 mg three times a day. For pediatric patients 20 kg to 45 kg, the recommended dosage is 20 mg three times a day. For pediatric patients 45 kg and greater, the recommended dosage is 20 mg three times a day. A maximum dose in pediatric patients has not been identified. Based on the experience in adults, dose may be titrated to a maximum of 40 mg three times a day for pediatric patients >45 kg, if required, based on symptoms and tolerability [see Clinical Studies (14) ] . 2.3 Reconstitution of the Powder for Oral Suspension Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by 30 mL) . Refer to the detailed instructions below. 1. Tap the bottle to loosen the powder. 2. Add 60 mL of water to the bottle. 3. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. 4. Add another 30 mL of water to the bottle. 5. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. 6. Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle. 7. Write the expiration date of the reconstituted oral suspension on the bottle label (the expiration date of the reconstituted oral suspension is 60 days from the date of reconstitution) . Incompatibilities Do not mix with any other medication or additional flavoring agent.

3 DOSAGE FORMS AND STRENGTHS REVATIO Tablets White, film-coated, round tablets engraved with “RVT20” containing sildenafil citrate equivalent to 20 mg of sildenafil. REVATIO for Oral Suspension White to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of water, the total volume of the oral suspension is 112 mL. A 2-mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. REVATIO Injection Single use vial containing 10 mg/12.5 mL of sildenafil. • Tablets: 20 mg ( 3 ) • For oral suspension: 10 mg/mL (when reconstituted) ( 3 ) • Injection: 10 mg/12.5 mL in a single use vial ( 3 )

4 CONTRAINDICATIONS REVATIO is contraindicated in patients with: • Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.1) ] . • Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. • Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. • Use with organic nitrates or riociguat. ( 4 ) • History of hypersensitivity reaction to sildenafil or any component of the tablet, injection, or oral suspension. ( 4 )

6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: • Hypotension [see Warnings and Precautions (5.1) ] • Vision Loss [see Warnings and Precautions (5.4) ] • Hearing Loss [see Warnings and Precautions (5.5) ] • Priapism [see Warnings and Precautions (5.7) ] • Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions (5.8) ] Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain and diarrhea. ( 6.1 , 6.2 ) Children: Priapism. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 REVATIO-treated adults with PAH (WHO Group I) [see Clinical Studies (14) ] the adverse reactions that were reported by at least 10% of REVATIO-treated patients in any dosing group, and were more frequent in REVATIO-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. The overall frequency of discontinuation in REVATIO-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation for placebo was 3%. Table 1. Most Common Adverse Reactions in Patients Treated with REVATIO 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in REVATIO-Treated Patients than Placebo-Treated Patients) REVATIO 20 mg (n = 69) REVATIO 40 mg (n = 67) REVATIO 80 mg (n = 71) Placebo (n = 70) Headache 46% 42% 49% 39% Flushing 10% 9% 16% 4% Pain in Limb 7% 15% 9% 6% Myalgia 7% 6% 14% 4% Back Pain 13% 13% 9% 11% Dyspepsia 13% 8% 13% 7% Diarrhea 9% 12% 10% 6% In a placebo-controlled fixed dose titration study (PACES-1) of REVATIO (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined REVATIO + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14) ] . In a study to assess the effects of multiple doses of REVATIO on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies (14) ] . Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies. Pediatric Patients REVATIO was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16‐week, double-blind placebo‐controlled study (STARTS-1); 220 patients continued in a long-term extension study (STARTS-2). Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4) ] . REVATIO Injection Adverse events with REVATIO injection were similar to those seen with oral tablets. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relation …

7 DRUG INTERACTIONS Nitrates Concomitant use of REVATIO with nitrates in any form is contraindicated [see Contraindications (4) ] . Strong CYP3A Inhibitors Concomitant use of REVATIO with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3) ] . Moderate-to-Strong CYP3A Inducers Concomitant use of REVATIO with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of REVATIO may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of REVATIO to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . • Use with strong CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) • Concomitant PDE-5 inhibitors: Avoid use with Viagra ® or other PDE-5 inhibitors. ( 5.6 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no‐observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of REVATIO to an infant during lactation. 8.4 Pediatric Use The safety and efficacy of REVATIO have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise Use of REVATIO for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1) , Clinical Studies (14) ] . The safety and effectiveness of REVATIO have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14) ] , an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324).Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg three times a day. 8.5 Geriatric Use Clinical studies of REVATIO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the …

12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo .

11 DESCRIPTION REVATIO, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. REVATIO (sildenafil) Tablets: REVATIO is formulated as white, film-coated round tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. REVATIO (sildenafil) Injection: REVATIO is supplied as a clear, colorless, sterile, ready to use solution in a single‐use vial containing 10 mg/12.5 mL of sildenafil. Each mL of solution contains 1.124 mg sildenafil citrate (equivalent to 0.8 mg sildenafil), 50.5 mg dextrose, and water for injection. REVATIO (sildenafil) for Oral Suspension: REVATIO is supplied as white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to1.12 g sildenafil) in an amber glass bottle intended for reconstitution. Following reconstitution with 90 mL water, the total volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include citric acid anhydrous, colloidal silicon dioxide anhydrous, grape flavor, sodium benzoate, sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide, and xanthan gum. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 0.5 mL and 2 mL dose markings) are provided. Sildenafil Citrate Structural Formula

10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

16 HOW SUPPLIED/STORAGE AND HANDLING REVATIO tablets are supplied as white, film-coated, round tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: REVATIO Tablets Package Configuration Strength NDC Engraving on Tablet Bottle of 90 Tablets 20 mg 0069-4190-68 RVT20 Recommended Storage for REVATIO Tablets: Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . REVATIO injection is supplied as a clear, colorless, sterile, ready to use solution containing 10 mg sildenafil/12.5 mL presented in a single-use glass vial. REVATIO Injection Package Configuration Strength NDC Vial individually packaged in a carton 10 mg /12.5 mL 0069-0338-01 Recommended Storage for REVATIO Injection: Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . REVATIO powder for oral suspension is supplied in amber glass bottles. Each bottle contains white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil). Following reconstitution, the total volume of the oral suspension is 112 mL (10 mg sildenafil/mL). A 2 mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press‐in bottle adaptor are also provided. REVATIO Powder for Oral Suspension Package Configuration Strength NDC Powder for oral suspension - bottle 10 mg/mL (when reconstituted) 0069-0336-21 Recommended storage for REVATIO for oral suspension: Store below 30°C (86°F) in the original package in order to protect from moisture. Recommended storage for reconstituted oral suspension: Store below 30°C (86°F) or in refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. The shelf-life of the reconstituted oral suspension is 60 days. Any remaining oral suspension should be discarded 60 days after reconstitution.